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排序方式: 共有3782条查询结果,搜索用时 15 毫秒
1.
Dr. Blijke S. Kroezen Gabriele Conti Benedetta Girardi Dr. Jonathan Cramer Dr. Xiaohua Jiang Dr. Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof. Daniel Ricklin Dr. Oliver Schwardt Prof. Beat Ernst 《ChemMedChem》2020,15(18):1706-1719
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. 相似文献
2.
Jasmin Kuhn Philipp M. Klein Nader Al Danaf Joel Z. Nordin Sren Reinhard Dominik M. Loy Miriam Hhn Samir El Andaloussi Don C. Lamb Ernst Wagner Yoshitsugu Aoki Taavi Lehto Ulrich Lchelt 《Advanced functional materials》2019,29(48)
Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile. 相似文献
3.
Dr. Wojciech Schönemann Dr. Jonathan Cramer Tobias Mühlethaler Dr. Brigitte Fiege Marleen Silbermann Dr. Said Rabbani Dr. Philipp Dätwyler Dr. Pascal Zihlmann Dr. Roman P. Jakob Dr. Christoph P. Sager Dr. Martin Smieško Dr. Oliver Schwardt Prof. Dr. Timm Maier Prof. Dr. Beat Ernst 《ChemMedChem》2019,14(7):749-757
Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar KD values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1H,15N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability. 相似文献
4.
In order to examine the impact of different Power-to-X technologies on the transformation of the German energy system and meeting the climate change mitigation goals, a cross-sectoral energy system model was developed. The results show that Power-to-X will be essential for a successful energy transition. Especially in applications where high energy densities are required and only few other options for defossilization exist, Power-to-X technologies become essential. 相似文献
5.
6.
This paper presents the results of experimental investigations and constitutive modeling of cyclic interface shearing between HDPE geomembrane and cohesionless sandy gravel. A series of cyclic interface shear tests was performed using a large-scale cyclic shear apparatus with servo controlled system. Particular attention was paid to the influences of the amount of shear-displacement amplitude, number of cycles, shear rate and the normal pressure on the mechanical response. The experimental results show that the path of the shear stress against the cyclic shear displacement is strongly non-linear and forms a closed hysteresis loop, which is pressure dependent, but almost independent of the shear rate. For small shear-displacement amplitudes, the obtained damping ratio is significantly greater than zero, which is different to the behavior usually observed for cyclic soil to soil shearing. In order to describe the pressure dependency of the hysteresis loop using a single set of constitutive parameters, new approximation functions are put forward and embedded into the concept of the Masing rule. Further, a new empirical function is proposed for the damping ratios to capture the experimental data for both small and large cyclic shear-displacement amplitudes. The included model parameters are easy to calibrate and the new functions may also be useful in developing enhanced constitutive models for the simulation of the cyclic interface shear behavior between other geosynthetics and soils. 相似文献
7.
This introduces an organic–inorganic thermosetting hybrid resin system based on unsaturated polyester and polysilazanes. It shows the chemical modification of unsaturated polyester structures by end capping to enable the combination of both components. In general, halogen‐free unsaturated polyesters are not fire‐retardant and have to be equipped with additives. Fillers and intumescent additives are preponderantly used in today's fire‐retardant formulations. In contrast to these fire‐retardants, polysilazanes act as ceramizing agents. Polysilazanes are suitable fire‐retardants for resin transfer molding due to their low viscosity. Both burning behavior and glass transition temperature (Tg) are investigated as important application properties. In contrast to state‐of‐the‐art fire‐retardant formulations polysilazane‐based thermosetting hybrid resins burn with high intensity and fast extinction. Therefore, total heat and smoke emission is decreased. The formation of ceramic structures during burning results in high residual mechanical properties and a low mass loss. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40375. 相似文献
8.
Folgen des Globalen Wandels für das Grundwasser in Süddeutschland – Teil 2: Sozioökonomische Aspekte
Dr. Roland Barthel Dr. Tatjana Krimly M. Sc. Michael Elbers Dr. Anja Soboll Dr. Johann Wackerbauer Prof. Dr. Rolf Hennicker Dr. Stephan Janisch Dr. Tim G. Reichenau Prof. Dr. Stephan Dabbert Prof. Dr. Jürgen Schmude Prof. Dr. Andreas Ernst Prof. Dr. Wolfram Mauser 《Grundwasser》2011,16(4):259-268
In order to account for complex interactions between humans climate and the water cycle, the research consortium GLOWA-Danube (www.glowa-danube.de) has developed the simulation system DANUBIA which consists of 17 coupled models. DANUBIA was applied to investigate various impacts of global-change between 2011 and 2060 in the Upper Danube Catchment. This article describes part 2 of an article series with investigations of socio-economic aspects, while part 1 (Barthel et al. in Grundwasser 16(4), doi:10.1007/s007-011-01794, 2011) deals with natural-spatial aspects. The principles of socio-economic actor-modeling and interactions between socio-economic and natural science model components are described here. We present selected simulations that show impacts on groundwater from changes in agriculture, tourism, economy, domestic water users and water supply. Despite decreases in water consumption, the scenario simulations show significant decreases in groundwater quantity. On the other hand, groundwater quality will likely be influenced more severely by land use changes compared to direct climatic causes. However, overall changes will not be dramatic. 相似文献
9.
Dunn AM Julien G Ernst WR Cook A Doe KG Jackman PM 《The Science of the total environment》2011,409(5):868-882
To minimize the risk posed by runoff from row crops, Prince Edward Island introduced buffer legislation in 2000. The legislation mandates 10-m and 20-m buffers, respectively, for moderate sloped (i.e. < 5%) and steep sloped (i.e. > 5%) agricultural fields that border streams. Since 2001, Environment Canada has been evaluating the effectiveness of various buffer widths on operational farms in reducing toxicity and contaminant concentrations in runoff. Sample collectors, placed in 44 fields at the field edge (0 m), 10 m and at distances out to 30 m, collected overland flow following rainfall-induced runoff events. Samples were collected within 24 hours of an event and analysed for seven pesticides (endosulfan, chlorothalonil, carbofuran, linuron, metribuzin, metalaxyl, mancozeb), water quality parameters and Daphnia magna toxicity. The 10-m buffer required for moderate sloped fields was effective at reducing contaminant concentrations but not always to less than lethal concentrations to Daphnia magna. Limited data beyond 10 m for fields of both slope types precluded making recommendations on a suitable buffer width for shallow sloped fields and evaluating the effectiveness of 20-m buffers for steep sloped fields. When paired data were combined and statistically tested for all fields, the studied pesticides underwent a 52-98% and 68-100% reduction in aqueous and particulate concentrations within 10 m and 30 m, respectively. In addition, by 10 m, soluble phosphorus, nitrate-nitrogen and total suspended solids were reduced by 34%, 38% and 64%, respectively. Results suggest buffer zones on operational farms are capable of achieving contaminant reductions comparable to those reported for controlled experiments. Inconsistent siting of sample collectors beyond 10 m limited the evaluation of the effects of field slope and buffer width on buffer effectiveness on working farms. Future studies on buffer efficiency on operational farms should focus on building the data set beyond 10 m and evaluating load reductions. 相似文献
10.
Impact of coagulation and adsorption on DOC fractions of secondary effluent and resulting fouling behaviour in ultrafiltration 总被引:2,自引:0,他引:2
Membrane fouling by macromolecular dissolved organic compounds is still a fundamental drawback in low-pressure membrane filtration of secondary effluent. In this study, pre-treatment of secondary effluent by coagulation and/or adsorption was investigated in terms of removal of different dissolved organic carbon (DOC) fractions, especially macromolecular substances. DOC fractionation has been characterised by size exclusion chromatography. Adsorption tests using four commercially available activated carbons yielded a removal of small as well as larger organic compounds, revealing differences in the affinity towards macromolecules depending on the type of applied activated carbon. By contrast, coagulation removed predominantly larger molecules, i.e., biopolymers and humic substances. In terms of DOC reduction, the coagulant ferric chloride was superior to aluminium chloride. A combination of coagulation and adsorption resulted in the addition of individual removal efficiencies, suggesting that different fractions of organic compounds were involved in each of the processes. After removal of macromolecular organic compounds either by coagulation or by adsorption, a significant reduction of membrane fouling was observed in tests using two different types of ultrafiltration flat-sheet membranes in 20-h cross-flow filtration tests. 相似文献